Abstract B147: P-Rex1 is required for efficient melanoma metastasis
| العنوان: | Abstract B147: P-Rex1 is required for efficient melanoma metastasis |
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| المؤلفون: | Richard L. Mort, Enda W. McDermott, Andrew D. Campbell, Léon C van Kempen, Kieran Sheahan, Ang Li, Patrizia Cammareri, William Gallacher, Paul Timpson, Owen J. Sansom, Ian G. Murphy, Brad Ozanne, Lionel Larue, Heidi C.E. Welch, Colin R Lindsay, Samuel Lawn, Channing J. Der, Mairin Rafferty, William J. Faller, Friedrich Beermann, Florian Rambow |
| المصدر: | Molecular Cancer Therapeutics. 10:B147-B147 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Cancer Research, business.industry, Melanoma, Intravasation, Cancer, medicine.disease, Metastasis, Oncology, Tumor progression, Melanoblast, Immunology, medicine, Cancer research, Immunohistochemistry, Genetically modified animal, business |
| الوصف: | Background: P-Rex1 is a Rac-specific Rho GTPase guanine nucleotide exchange factor that has recently been implicated in cancer for the first time. As Rac has a central role in control of cell motility, we assessed the role of P-Rex1 in melanoma, a cancer where metastasis is the major cause of death. This was the first evaluation of P-Rex1 in a genetically modified animal model of cancer. We also investigated the function of P-Rex1 in melanoblasts, as the molecular pathways that drive their developmental migration are believed to underpin the movement of metastatic melanoma cells. Methods: P-Rex1−/− mice were crossed to mice carrying the DCT-lacZ transgene, a melanoblast reporter line, and a Tyr::NrasQ61K/°; INK4a−/− metastatic melanoma mouse model. Allograft tail vein (TV) injections were performed to further assess the endogenous function of P-Rex1 in metastasis. Panels of human melanoma cell lines and tissue were investigated with microarray, tissue culture, and immunohistochemical techniques. Results: P-Rex1−/− mice have a melanoblast migration defect during development (p=0.01), evidenced by a white belly. They were resistant to metastasis when crossed to the Tyr::NrasQ61K/°; INK4a−/− murine model of melanoma (1/30 mice with metastases vs 13/30 in control cohort; p=0.001). When melanocytes derived from this model were TV-injected into immune-competent allografts, endogenous P-Rex1 was found to facilitate metastatic incidence, growth, and organ spread following the intravasation stage of the metastatic cascade (p=0.02). Mechanistically, this was associated with P-Rex1 driving invasion in a Rac-dependent manner. In humans, P-Rex1 was elevated in the great majority of melanoma cell lines, with mRNA levels above the median statistically associated with metastasic propensity (p=0.005). Tissue immunohistochemistry revealed an association between tumor progression and P-Rex1 expression. Conclusions: P-Rex1 is a key component of melanoma progression, invasion and metastatic signaling, supporting the value of pharmacological inhibition of P-Rex1 activation of Rac for treatment of metastatic or high risk primary melanomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B147. |
| تدمد: | 1538-8514 1535-7163 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::8e6257703eb75ee3aa1b4a70a48d5578Test https://doi.org/10.1158/1535-7163.targ-11-b147Test |
| رقم الانضمام: | edsair.doi...........8e6257703eb75ee3aa1b4a70a48d5578 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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